WO2007110981A1 - External preparation for skin - Google Patents

Abstract

It is intended to provide an external preparation for skin which improves coarsening of skin texture, wrinkles and sagging skin. The external preparation for skin of the invention is characterized by containing nonylic acid vanillylamide at 0.0001% by mass or more and 0.05% by mass or less based on the total of external preparation for skin as an active ingredient and is useful for improving coarsening of skin texture, wrinkles and sagging skin.

Description

 Specification

 Skin preparation

 Technical field

 [0001] The present invention relates to a skin external preparation, and more particularly, to a skin external preparation containing nonyl acid vanillylamide.

 Background art

 [0002] Disorders of skin texture, wrinkles, or sagging skin (loss of elasticity) are caused by aging or stress due to aging. That is, skin tissue degeneration due to aging, stress, etc., especially interstitial substances such as collagen, elastin and hyaluronic acid are greatly lost, which is mainly caused by skin texture disturbance, wrinkles or sagging skin. This can cause skin dullness as a result. Vitamin A and steroids have been used to improve skin sagging. In recent years, cosmetics containing coenzyme Q10 have been known as a coenzyme called coenzyme Q10 (also known as ubiquinone) has the effect of preventing skin aging. However, the above-mentioned action of Coenzyme Q10 is based on suppressing the production of lipid peroxide, and Coenzyme Q10 is not directly involved in the production of collagen, elastin or hyaluronic acid.

 [0003] Nonyl acid vanillylamide has been conventionally blended into skin external preparations, poultices and the like for the purpose of warming action or blood circulation promoting action (see, for example, Patent Documents 1 and 2). Furthermore, noninolic acid vanillylamide is also used as an additive for cosmetics such as hair care products for the purpose of stimulating the skin to promote blood circulation and the purpose of stimulating hair roots.

 [0004] Further, a rough skin treatment preparation and a rough skin treatment patch (Patent Document 3), which are effective in cracking and scuffing, containing nonyl acid vanillylamide and humectant glycerin are known. However, Patent Document 3 states that nonyl acid vanillylamide is effective in improving skin texture disturbance and skin sagging, or is involved in the production of interstitial substances such as collagen, elastin or hyaluronic acid. There is no mention of increasing the production of substances.

 Patent Document 1: Japanese Patent Application Laid-Open No. 2005-343915

Patent Document 2: JP 2005-306831 Patent Document 3: Japanese Patent Laid-Open No. 2002-167335

 Disclosure of the invention

 Problems to be solved by the invention

[0006] An object of the present invention is to provide an external preparation for skin that improves skin texture disorder, wrinkles, or skin sagging.

 Means for solving the problem

[0007] The inventors of the present invention conducted intensive research to solve the above-mentioned problems. As a result, when a topical skin preparation containing nonyl acid vanillylamide was applied to the face, the skin texture was disturbed, and the face of the face of the face of the face was damaged. It was found that significant improvement was observed in sagging of nya. The inventors have further researched and completed the present invention.

That is, the present invention provides:

 [1] Improves skin texture, wrinkles or sagging characterized by containing nonyl acid vanillylamide as an active ingredient in an amount of 0.0001% by mass to 0.05% by mass based on the total amount of external preparations for skin Skin external preparation,

 [2] The external preparation for skin according to [1] above, which is an external preparation for improving skin texture disorder, [3] The external preparation for skin improvement according to [3] for improving wrinkles or skin sagging Skin external preparation,

 [4] The skin external preparation according to any one of [1] to [3], further comprising a nonionic surfactant,

 [5] Formulation power S of nonyl acid vanillylamide and nonionic surfactant S, nonionic surfactant 50 to 30000 parts by mass with respect to 1 part by mass of nonyl acid vanillinoleamide External application for skin according to the above [4] Agent,

[6] Nonionic surfactant power Polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkyl phenyl ether and The skin external preparation described in [4] or [5] above, which is at least one selected from polyoxyethylene sorbite fatty acid esters, [7] The skin external preparation is in the form of liquid, suspension, emulsion, cream, ointment, gel, liniment, lotion, poultice or pack [1] to [6] a topical skin preparation according to any one of

 [8] The skin external preparation according to any one of [1] to [7], wherein the skin external preparation is a cosmetic.

[0009] The present invention also provides:

 [9] Applying an external skin preparation containing 0.001% by mass or more and 0.05% by mass or less of nonyl acid vanillylamide as an active ingredient to the skin of mammals including humans. Characteristic skin texture improvement method, skin wrinkle improvement method or skin sagging improvement method,

 About.

 The present invention also provides:

 [10] To improve skin texture disturbance, wrinkle improvement, or skin sagging containing nonyl acid vanillylamide as an active ingredient in an amount of 0.0001% by mass to 0.05% by mass based on the total amount of external preparation for skin Use of noelic acid vanillylamide for the preparation of a topical skin preparation.

 The invention's effect

 [0010] The external preparation for skin of the present invention has a beautifying effect such as adjusting the texture of the skin, and also improves the sagging of the skin. The preparation of the above-mentioned texture includes the ability to improve the irregularity of the texture of the skin and the like.

 [0011] In addition, the external preparation for skin of the present invention can be used for safely improving skin texture disturbance without causing irritation to the skin by blending nonylic acid vanillylamide and a specific nonionic surfactant. It can be used as an external skin preparation for improving wrinkles and skin sagging.

 Brief Description of Drawings

 FIG. 1 is a diagram showing a place where a test substance is applied in Test Example 3.

 FIG. 2 is a diagram showing a test schedule in Test Example 3.

[FIG. 3] FIG. 3 is a graph showing the transition of the texture volume ratio (relative value). In the figure, * indicates a significant difference from cream B (P <0. 05). [FIG. 4] FIG. 4 is a graph showing the transition of the number of textures (relative value). In the figure, * indicates a significant difference (P <0.05) for cream B, and ** indicates a significant difference for cream B (P <0.01).

 [FIG. 5] FIG. 5 is a graph showing changes in the volume ratio (relative value) of the wrinkles. In the figure, * indicates a significant difference with respect to cream B (P <0. 05), and * * indicates a significant difference with respect to cream B (P <0.01).

 [Fig. 6] Fig. 6 is a graph showing the transition of the number of sheets (relative value). In the figure, * indicates a significant difference from cream B (P <0. 05).

 [FIG. 7] FIG. 7 shows the blood flow on the skin surface of the inner forearm before and 30 minutes after application of the cream. The vertical axis shows the relative value (ratio) with the value before application being 1.

 [Fig. 8] Fig. 8 shows the texture of a cocoon photographed by a super skin checker MC—SSC built-in CCD camera. Before application, the texture of wrinkles before cream application is shown, and after 1 week of application, the texture of wrinkles after 1 week of application is shown.

 [FIG. 9] FIG. 9 shows the corners of the corner of the eye taken using a digital camera EOS—Kiss Digital N (Canon, Inc.). Before application, it shows the corners of the corners of the eyes before application of the cream, and after one week of application, it shows the spots of the corners of the corners of the eyes after application of the cream.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail.

 Nonyl acid vanillylamide (Hydroxy-3-methoxybenzyl nonilic acid amide) used in the present invention is also referred to as nonyl acid nylylamide, and is, for example, according to the method described in J. Med. Chem., 1993, 36, 2595. Can be manufactured.

[0014] The concentration of nonylic acid vanillylamide in the external preparation for skin of the present invention is not particularly limited as long as it is a concentration capable of exhibiting the effects of the present invention. However, since nonylic acid vanillylamide is a substance having strong local irritation, it is preferable that the concentration is non-irritating at the site of administration in consideration of the irritation. For this reason, the lower limit of the nonyl acid vanillylamide concentration in the external preparation for skin of the present invention is preferably about 0.0001% by mass relative to the total external preparation for skin, and the upper limit for 0.0005% by mass is more preferably about 0.001%. About 0.025% by mass, more preferably 05% by mass, is more preferable. A more specific concentration of nonyl acid vanillylamide is preferably about 0.0001% by mass or more and 0.05% by mass or less of nonyl acid vanillyl amide with respect to the whole external preparation for skin. More preferably, the amount is about 0.0001% by mass or more and 0.025% by mass or less.

[0015] The external preparation for skin of the present invention preferably contains a nonionic surfactant in nonyl acid vanillylamide. Nonionic surfactants include, for example, polyoxyethylene castor oil [eg, polyoxyethylene (3) castor oil, polyoxyethylene (10) castor oil, polyoxyethylene (20) castor oil, polyoxyethylene (40) castor oil]. Oil, polyoxyethylene (50) castor oil, polyoxyethylene (60) castor oil, etc.], polyoxyethylene hydrogenated castor oil [eg, polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil Oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (80) hydrogenated castor oil, etc.], polyethylene glycol fatty acid ester (eg, polyethylene glycol monolaurate, polyethylene glycol monostearate) , Polyethylene glycol monooleate, polyethylene distearate Glycol, diisostearic acid polyethylene glycol, etc.), polyoxyethylene alkyl ether [eg, polyoxyethylene (25) lauryl ether, polyoxyethylene (15) cetyl ether, polyoxyethylene (4) stearyl ether, polyoxyethylene (20) Rail ether, etc.], polyoxyethylene polyoxypropylene alkyl ether (eg, poloxamer 235), polyoxyethylene alkyl phenyl ether (eg, polyoxyethylene (7.5) nonyl phenyl ether, polyoxyethylene (3 ) Octylphenyl ether etc.] or polyoxyethylene sorbite fatty acid ester [eg polyoxyethylene (60) sorbite, polyoxyethylene (6) sorbite monolaurate, polyoxyethylene (6) sorbitol tetraoleate) And the like. Among them, polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil or polyoxyethylene (80) hydrogenated castor Especially preferred are polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil or polyoxyethylene (60) hydrogenated castor oil. Nonionic surfactants can be used singly or in combination of two or more. By adding a nonionic surfactant to the external preparation for skin, irritation to the skin of nonylic acid vanillylamide can be alleviated.

[0016] The blending amount of the nonionic surfactant depends on the nonionic surfactant used. Although it is different, about 18% by mass or more, more preferably about 9% by mass or more, more preferably about 5% by mass or more is more preferable with respect to the whole external preparation for skin. The upper limit of these nonionic surfactants varies depending on the nonionic surfactant used, but is preferably about 30% by mass, more preferably about 20% by mass.

 [0017] In the external preparation for skin of the present invention, the combination ratio of nonylic acid vanillylamide and the nonionic surfactant varies depending on the nonionic surfactant used, but usually 1 part by weight of nonylic acid vanillylamide. The nonionic surfactant is about 50 to 30000 parts by mass, preferably about 360 to 3600 parts by mass.

 [0018] Examples of the external preparation for skin having the above blending ratio include, for example, nonyl acid vanillylamide of about 0.0001% by mass to 0.05% by mass and polyoxyethylene hydrogenated castor oil of about 5% by mass to 30% by mass. A preferred example is a formulation containing about 0.0001% by mass or more and 0.05% by mass or less of nonyl acid vanillylamide and about 9% by mass or more and 20% by mass or less of polyoxyethylene hydrogenated castor oil. As mentioned.

 [0019] Preferred examples of the external preparation for skin of the present invention include pharmaceuticals or quasi-drugs such as liquids, suspensions, emulsions, creams, ointments, gels, liniments, lotions, and poultices. . Moreover, cosmetics are contained in the skin external preparation of this invention. Examples of cosmetics include skin lotions, cosmetic emulsions, cosmetic creams, cosmetic gels, cosmetic lotions, skin care products such as preparations, foundations, facial cleansers, body soaps, hand creams, and makeup products. Can be mentioned.

 [0020] According to the dosage form, the external preparation for skin of the present invention is prepared by adding, for example, the following base components and additives to nonyl acid vanillylamide and the nonionic surfactant, and mixing these components. Manufactured. In that case, it can be produced according to a known method, for example, the method described in the 14th revised Japanese Pharmacopoeia General Rules for Preparations, or the like. Nonyl acid vanillylamide is hardly soluble in cold water, but is well soluble in oil and alcohol. Therefore, the preparation of the external preparation for skin of the present invention is produced by containing a component in which nonyl acid vanillylamide is well soluble as a base. It is preferable.

[0021] When the external preparation for skin of the present invention is a liquid preparation, a liquid preparation can be produced by adding, for example, a solvent to nonyl acid vanillylamide and the nonionic surfactant and mixing and dissolving them. [0022] When the external preparation for skin of the present invention is a suspension, for example, water and suspending agent or thickener are added to nonyl acid vanillylamide and the nonionic surfactant, and the mixture is stirred with, for example, a mixer. In addition, the suspension can be produced with the same quality.

 [0023] When the skin external preparation of the present invention is an emulsion, nonyl acid vanillylamide and the nonionic surfactant are mixed with, for example, an emulsifier, a fatty oil, and water, and stirred with a homomixer, for example. Emulsions can be produced with equality.

 [0024] When the external preparation for skin of the present invention is a cream, for example, an oily component, a higher alcohol, a higher fatty acid, a polyhydric alcohol, water and the like are added to nonyl acid vanillylamide and the nonionic surfactant. For example, a cream can be produced by emulsifying while heating and then cooling with stirring.

 [0025] When the external preparation for skin of the present invention is an ointment, for example, an oily component or the like is used as a base as it is, or an oily component, a resin, a plastic (eg, microcrystalline wax, polyethylene powder, etc.), glycol , Higher alcohol, water and emulsifier or suspending agent, etc. emulsified in the same manner as the above cream, and nonyl acid vanillylamide and the above nonionic surfactant are added to the base and mixed. Ointments can be produced with the same quality.

 [0026] The emulsion, cream, or emulsified ointment includes oil-in-water (O / W) type, water-in-oil (W / O) type, W / 0 / W type, 0 / W / 0 type, etc. Any of the listed powers is not particularly limited.

 [0027] Further, when the skin external preparation of the present invention is a gel, for example, water, higher alcohol, gelling agent, etc. are used as a base component, and together with these base components nonyl acid vanillylamide and the nonionic surfactant It is possible to produce a gel by dissolving the agent by heating and cooling it with stirring.

 [0028] When the external preparation for skin of the present invention is a liniment, nonyl acid vanillylamide and the nonionic surfactant are added to, for example, ethanol, fatty oil, emulsifier or suspending agent, or a mixture thereof. A liniment can be produced by mixing and adding an essential oil component such as menthol to make it evenly mud.

[0029] When the external preparation for skin of the present invention is a lotion, for example, ethanol, higher alcohol A lotion preparation can be produced by adding nonyl acid vanillylamide and a nonionic surfactant to an alcohol, an emulsifier, a suspending agent, and the like and mixing them to make the whole quality uniform.

 [0030] When the skin external preparation of the present invention is a cataplasm, nonyl acid vanillylamide and the nonionic surfactant described above are mixed with, for example, concentrated glycerin and the like, and an essential oil component such as menthol is added to uniformly distribute the whole quality. It is possible to produce a poultice by making it mud.

 [0031] Examples of the solvent include water, physiological saline, isopropanol, concentrated glycerin, ethanol, propylene glycol, and Macrogol 400. Examples of water include normal water, purified water, distilled water, hard water, soft water, natural water, deep ocean water, electrolytic alkaline ionized water, electrolytic acidic ionized water, ionic water, or cluster water.

 [0032] Examples of the suspending agent, thickening agent, or gelling agent include gum arabic, aluminum monostearate, and water-soluble polymers [for example, methylcellulose, hydroxypropylcellulose, hydroxypropinoremethinoresenorelose, canolemellose. , Canolemellose sodium, strength nomellose calcium, popidone, carboxyvinyl polymer (Carbopol 941; manufactured by Noveon, Inc .; also referred to as carbomer)] and the like.

 [0033] Examples of the emulsifier include polyoxyl 40 stearate, sorbitan sesquioleate, polysorbate 80, sodium ralyl sulfate, lauromacrogol, gum arabic, cholesterol, stearic acid, glyceryl monostearate, and popidone.

 [0034] Examples of the fatty oils include synthetic oils such as medium-chain fatty acid triglycerides and hard fats, coconut oil, palm oil, palm kernel oil, safflower oil, olive oil, castor oil, avocado oil, sesame oil, Tea oil, evening primrose oil, wheat germ oil, macadamia nut oil, hazelnut oil, cucumber nut oil, rosehip oil, meadowweed oil, persic oil, tea tree oil, hearth oil, corn oil, rapeseed oil, castor oil, wheat germ oil Amani oil, cottonseed oil, soybean oil, peanut oil, rice bran oil, squalene, etc., or hardened oils thereof.

[0035] Examples of the oil component include, for example, the above fatty oils; liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, α-olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive Hydrocarbons such as squalane, squalene, petrolatum, solid paraffin; candelilla wax, carnauba wax, rice wax, wax, beeswax, beeswax, montan wax, ozokerite, ceresin, paraffin Wax, microcrystalline wax, petrolatum, Fischer-Tropsch wax, waxes such as polyethylene wax, ethylene propylene copolymer; animal fats such as beef tallow, milk fat, horse fat, egg yolk oil, mink oil, tartonole oil; whale wax, Animal waxes such as lanolin, orange luffy oil, etc .; or liquid lanolin, reduced lanolin, adsorbed purified lanolin, lanolin acetate, liquid lanolin acetate, hydroxy lanolin, polyoxyethylene lanolin, lanolin fatty acid

Lanolins such as hard lanolin fatty acid, lanolin alcohol, lanolin alcohol acetate, and acetic acid (cetyl'lanolyl) ester.

 [0036] Examples of the higher alcohol include cetanol, myristino-leanolecole, oleil ano-reconole, laurino-reno-reconole, cetostearino-reno-reconole, stearino-leano-reconole, araquinole- nore-conole, Examples include henino-leanolone, jojobano-reconole, kimino-leno-conole, selalkyl alcohol, batyl alcohol, hexyldecanol, isostearyl alcohol, 2-octyldodecanol, and dimer diol.

 [0037] Examples of the higher fatty acid include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, undecylenic acid, 12-hydroxystearic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, Examples include L-force acid, docosahexaenoic acid, eicosapentaenoic acid, isohexadecanoic acid, long-chain branched fatty acid, dimer acid, or hydrogenated dimer acid.

 [0038] Examples of the polyhydric alcohol include propylene glycol, polyethylene glycol, glycerin, 1,3-butylene glycol and the like.

 [0039] In addition, the skin external preparation of the present invention may optionally contain any component that can be used in pharmaceuticals, quasi drugs, cosmetics, and the like, such as antioxidants, preservatives, stabilizers (or chelating agents), and amphoteric. Surfactants, cationic surfactants, moisturizers, reducing agents, pH adjusters, powders, UV absorbers, whitening agents, buffering agents or inorganic salts, propellants, lower alcohols (eg ethanol, isopropanol, etc.) , Fresheners, astringents, fragrances, fragrances or pigments may be combined.

[0040] Examples of the antioxidant include platinum nanocolloid (platinum), tocopherol (vitamin E), tocopherol acetate, etc., dibutylhydroxytoluene, dibutylhydroxyanisole, vitamin C (ascorbic acid) or a derivative thereof, Erythorbic acid or its derivatives, Examples thereof include sulfites such as sodium sulfite, bisulfites such as sodium hydrogen sulfite, thiosulfates such as sodium thiosulfate, metabisulfite, thiotaurine, hypotaurine; thioglycerol, thiourea or thioglycolic acid.

 [0041] Examples of the preservatives include hydroxybenzoic acid such as methylparaben, ethylparaben, propylparaben, and butylparaben or salts or esters thereof; salicylic acid; sodium benzoate; phenoxyethanol; 1,2-diols such as 1,2-hexanediol; isothiazolinone derivatives such as methyl isothiazolinone and methylisothiazolinone; imidazolinium urea; dehydroacetic acid or salts thereof; phenols; benzalkonium chloride, chloride Quaternary ammonium salts such as benzethonium; halogenated bisphenols such as triclosan, acid amides; trichlorocarbanide, zinc pyrithione, sorbic acid, chlorhexidine, chlorhexidine dalconate, halocarban F Emissions, Hinokichionore, Chimonore, Roh Norakuro port Fuenonore, Fueninoreechi alcohol include antimicrobial Zeoraito or silver ions and the like.

 [0042] Examples of the stabilizer (or chelating agent) include edetic acid (ethylenediamine tetraacetic acid), disodium edetic acid, trisodium edetic acid, tetrasodium edetic acid, hydroxyethyl diamine diacetic acid triacetate, and pentet. Acid salts (diethylenetriaminepentaacetate), phosphonic acids such as phytic acid, etidronic acid, or salts thereof such as sodium oxalate, polyaspartic acid, polygnoletamic acid, sodium polyphosphate, sodium metaphosphate, phosphoric acid, citrate Examples include sodium citrate, citrate, alanine, dihydroxyethylglycine, darconic acid, asconolevic acid, succinic acid, tartaric acid, tocopherol acetate, dibutylhydroxytoluene, dimethylpolysiloxane, diethanolamine, and triethanolamine. It is done.

[0043] Examples of amphoteric surfactants include alkyldimethylaminoacetic acid betaines (eg, laurinore dimethylaminoacetic acid betaine, coconut oil fatty acid amidopropyldimethylaminoacetic acid betaine) and the like.

 [0044] Examples of cationic surfactants include alkyl ammonium salts (eg, cetyltrimethylammonium chloride, stearyltrimethylammonium chloride, dioctyldimethylammonium chloride, salt-distearyldimethylammonium chloride). Etc.).

[0045] Examples of the humectant include glycerin, 1,3-butylene glycol, and propylene glycol. Nore, 3-methyl-1,3 butanediol, 1,3 propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, pentaerythritol, hexylene glycol, diglycerin, polyglycerin, diethylene glycol, polyethylene glycol, di- Polyols such as propylene glycol, polypropylene glycol, and ethylene glycol / propylene glycol copolymers or polymers thereof; diethylene glycol monoethyl ethenole (ethoxy diglycol nore), ethylene glycol monoethanolino ethenore, ethylene Glyconorenorequinoleatenoles such as glyconolemonobutinoreethenore and diethyleneglyconoresibutinoreatenore; Sonorebitonore, Xylitonore, Erythritono Sugar alcohols such as mannitol, mannitol, maltitol; glucose, fructose, galactose, mannose, throse, xylose, sorbit, arabinose, fucose, ribose, deoxyribose, manoletos, trehalose, ratatose, raffinose, gnoreconic acid, gnoreconic acid, cyclone Dextrins (Hiichi, β_, γ cyclodextrins, or modified cyclodextrins such as maltosylated or hydroxyalkylated), β-glucans, chitin, chitosan, heparin or derivatives thereof, pectin, arabinogalatatan, Sugars or derivatives thereof such as dextrin, dextran, glycogen, ethyldanolecoside, darcosinoretyl methacrylate polymer or copolymer; hyaluronic acid, sodium hyaluronate Chondroitin sulfate sodium; mucoitin sulfate, caroline sulfate, kerato sulfate, dermatan sulfate; organic acids such as citrate, tartaric acid and lactic acid or salts thereof; urea; salts of 2 pyrrolidone 5 strength rubonic acid or sodium thereof; Betaine (trimethylglycine), proline, hydroxyproline, arginine

, Lysine, serine, glycine, alanine, phenylalanine, tyrosine, β-alanine, threonine, gnoretamic acid, gnoletamine, asparagine, aspartate, cysteine, cystine, methionine, leucine, isoleucine, valine, tryptophan, histidine, taurine, etc. Amino acids or salts thereof; collagen, fish-derived collagen, atelocollagen, gelatin, elastin, collagen-degrading peptide, hydrolyzed collagen, hydroxypropyl ammonium hydrolyzed collagen, elastin-degrading peptide, keratin-degrading peptide, hydrolyzed keratin, conkyolin degrading Peptide, hydrolyzed conchiolin, silk protein degrading peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soy proteolytic peptide, wheat White decomposition peptide, hydrolyzed wheat protein, casein hydrolysates, Ashinore Protein peptides such as lysed peptides or their derivatives; acylated peptides such as palmitoyl oligopeptides, palmitoyl pentapeptides, palmitoyl tetrapeptides; silylois peptides; Gland mucin, hippoturin, sesame lignan glycoside, dartathione, anolebumin, whey; choline chloride, phosphorinole choline; placenta extract, aerostin, collagen, aloe extract, hamamelis water, hechima water, force momilla extract, licorice extract, comfrey Extracts, silk extracts, izayo balaekis, sorghum extract, eucalyptus extract, merirot extract and other animal or plant extract components, natural ceramides (types 1, 2, 3, 4, 5, 6), hydroxyceramides, pseudo Ceramics, Sufine Glycolipid or ceramide, and the like.

 [0046] Examples of the pH adjuster include citrate, sodium citrate, lactic acid, sodium lactate, dallic acid, succinic acid, acetic acid, sodium acetate, malic acid, tartaric acid, fumaric acid, phosphoric acid, hydrochloric acid, sulfuric acid, Monoethanolamine, diethanolamine, triethanolamine, isopropanolanolamine, triisopropanolamine, 2-amino-1-methylenole 1,3-propanediol, 2-amino-2-hydroxymethyl-1,3-propane Examples include diol, arginine, sodium hydroxide, potassium hydroxide, aqueous ammonia, guanidine carbonate, sodium hydrogen carbonate, ammonium carbonate, and the like.

[0047] Examples of the powders include my strength, talc, kaolin, sericite, montmorillonite, kaolinite, mica, muscovite, phlogopite, synthetic mica, sauroite, biotite, permkyrite, magnesium carbonate, carbonic acid. Calcium, aluminum silicate, barium silicate, calcium silicate, magnesium silicate, strontium silicate, metal tungstate, magnesium, zeolite, barium sulfate, calcined calcium sulfate, calcium phosphate, fluorapatite, hydroxyapatite, ceramic Powder, titanium oxide, zinc oxide, alumina, silica mica titanium, fish scale foil, pearl pigment, kappa powder, urethane powder, silicone powder, yellow iron oxide, black iron oxide, carbon black, mango violet, cobalt violet, chromium oxide, Chromium oxide, ultramarine, bentonite, nylon powder, polyester powder, polyethylene powder, polystyrene powder, cellulose powder, red 201, red 202, red 205, red 220, red 226, red 405, orange 203 , Yellow 2 05, Yellow 401 and Blue 404 and other organic pigments, Red 3, Red 104, Red 227 No., Red No. 401, Red No. 505, Orange No. 205, Yellow No. 4, Yellow No. 202, Yellow No. 203, Green No. 3 and Blue No. 1 zirconium or aluminum lake.

Examples of the ultraviolet absorber include paraaminobenzoic acid, paraaminobenzoic acid monoglycerin ester, N, N-dipropoxyparaaminobenzoic acid ethyl ester, N, N-jetoxyparaaminobenzoic acid ethyl ester, N, N-dimethylparaaminobenzoic acid ethyl ester, Benzoic acid UV absorbers such as N, N-dimethylparaaminobenzoic acid butyl ester and N, N-dimethylparaaminobenzoic acid ethyl ester; Anthranilic acid UV absorbers such as homomenthyl N-acetyl anthranilate; Salicylic acid or its Salicylic acid UV absorbers such as salt, amyl salicylate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate Octyl cinnamate, ethinole-4-isopropyl cinnamate, methinole 2,5-diisopropyl cinnamate, ethyl _ 2, 4--methoxy cinnamate, isopropyl p methoxy cinnamate, isoamino les p methoxy cinnamate, 2-ethyl Hexyl p-methoxycinnamate (octyl p-methoxymethoxy arsenate), 2-ethoxychetyl p-methoxycinnamate (sinoxate), cyclohexyl —P-methoxycinnamate, ethyl-cyanate β-phenyl cinnamate, 2- Cinnamic acid UV absorbers such as tilhexyl α-cyano β ferrocinnamate (otatoclin), glyceryl mono-2-ethyl hexanoyl diparamethoxycinnamate, ferulic acid or its derivatives; 2, 4 dihydroxybenzophenone, twenty two '- Hydroxy 4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2,2 ', 4,4'-tetrahydroxybenzophenone, 2-hydroxy_ 4-methoxybenzophen Enone (oxybenzone-3), 2-hydroxy-1-4-methoxy-1-4'-methylbenzophenone, 2-hydroxy-1-methoxybenzophenone-5-sulfonate, 4-phenylbenzophenone, 2_ethylhexyl Benzophenone-based UV absorbers such as 1'4'-phenylbenzobenzoenone 2 _carboxylate, 2-hydroxy-1-4-η-octoxybenzophenone, 4-hydroxy-1-3-carboxy benzophenone; '—Methylbenzylidene)-d, 1 _ camphor, 3 _ benzylidene _ d, 1 _ camphor; 2-phenyl 1 5 _ methyl 2, 2-hydroxy 5-methylphenylbenzotriazole; 2- (2'-hydroxy 5'-t octylphenyl) benzotriazole; 2- (2'-hydroxy-5, monomethylphenylbenzotriazole; 5- (3,3 dimethyl-2-norbornylidene) -3-pentane-2-one; benzoylmethane derivatives such as 4_t_butyl_4-methoxybenzoylmethane; octyltriazone; urocanic acid or its derivatives; — (2'-hydroxy-5'-methylphenyl) benzotriazole, 1- (3,4-dimethoxyphenyl) -1,4,4-dimethyl-1,3-pentanedione, dimethoxybenzylidenedioxoimidazolidine Hydantoin derivatives such as 2_ethylhexyl propionate, phenylbenzimidazozo sulfonic acid, terephthalylidene dicamphor Sulfonic acid, drometrizole siloxanyl emissions, such as methyl anthranilate, or rutin or a derivative thereof.

 [0049] Examples of the whitening agent include hydroquinone glycosides such as arbutin and hi-arbutin or esters thereof; ascorbic acid or ascorbic acid phosphate ester salt such as ascorbic acid phosphate magnesium salt; Ascorbic acid fatty acid ester such as palmitic acid ester, ascorbic acid alkyl ether such as ascorbic acid ethyl ether, ascorbic acid dalcoside such as ascorbic acid 2-dalcoside or fatty acid esters thereof, ascorbic acid sulfate ester, ascorbic acid derivative such as tocopherylas corbyl phosphate And kojic acid, ellagic acid, tranexamic acid or derivatives thereof.

 [0050] Examples of buffers or inorganic salts include sodium chloride, potassium chloride, aluminum chloride, calcium chloride, magnesium chloride, zinc chloride, ammonium chloride, sodium sulfate, aluminum sulfate, aluminum sulfate 'potassium (Miyoban) , Aluminum sulfate, ammonium sulfate, barium sulfate, calcium sulfate, potassium sulfate, magnesium sulfate, zinc sulfate, iron sulfate, copper sulfate, monosodium phosphate, disodium phosphate, disodium hydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, phosphorus Examples include potassium phosphates, calcium phosphates, and magnesium phosphates.

[0051] Examples of the propellant include a liquefied gas propellant or a compressed gas. Examples of the liquefied gas propellant include fluorinated hydrocarbons (alternative chlorofluorocarbons such as HCFC22, HCFC_123, HCFC_134a, and HCF C142), liquefied petroleum, dimethyl ether, and the like. Compression Examples of the gas include soluble gas (carbon dioxide gas, nitrous oxide gas, etc.) or insoluble gas (nitrogen gas, etc.).

 [0052] Examples of the lower alcohol include ethanol, isopropanol, butanol, and isobutyl alcohol. Examples of the refreshing agent include menthol, camphor, borneol, heart power oil, camphor or rosemary oil. Examples of astringents include citrate, tartaric acid, lactic acid, aluminum sulfate potassium, and tannic acid. Examples of the fragrances include methyl salicylate, wikial oil, spruce tincture or dl_menthol.

 [0053] Cosmetics such as lotions, cosmetic emulsions, cosmetic creams, hand creams, packs lj, foundations, body soaps or facial cleansers are also mentioned above, for example liquids, creams ij, lotions or liniments, etc. It can be manufactured according to.

 [0054] The pack agent may be of a type in which the above-mentioned lotion or emulsion is infiltrated into, for example, a non-woven fabric and masked on the face, etc. Good.

 [0055] In the case of liquid preparations, suspensions, emulsions, creams, ointments, gels, liniments or lotions, the external preparation for skin itself can be directly applied to the skin. In the case of a poultice, for example, it can be applied or impregnated on the woven or non-woven fabric layer side of the support, and a liner such as a polypropylene film is further applied, and then applied to the skin.

[0056] The skin external preparation of the present invention, for example, in the case of a nonylic acid vanillylamide 0.005 mass ⁰ / _0- containing term agent, is about :! to 10 times a day, about 0. 2 · It is preferable to apply Og. In addition, the external preparation for skin of the present invention is preferably applied after face washing or bathing or before going to bed.

 [0057] The external preparation for skin of the present invention can also be combined with other medicinal ingredients without departing from the effects of the present invention. Examples of other medicinal ingredients include vitamins, anti-inflammatory analgesics, antihistamines, antipruritics and the like.

[0058] Examples of vitamins include vitamins A such as retinol, retinol acetate, and retinol palmitate; thiamine hydrochloride, thiamine sulfate, riboflavin, riboflavin acetate, pyridoxine hydrochloride, pyridoxine dioctanoate, pyridoxine dipalmi Tate, Flavina Vitamin B group of denine dinucleotide; cyanocobalamin; folic acid; nicotinic acid amide, nicotinic acid such as benzilate benzil; vitamin C such as ascorbic acid or its salt; vitamin D; ct, β γ, δ-Vitamins such as tocopherols; pantothenic acid; biotin; ascorbic acid phosphate sodium salt or ascorbic acid phosphate magnesium salt such as ascorbic acid phosphate salt, ascorbic acid tetraisopalmitate, stearic acid Ascorbic acid fatty acid esters such as ascorbyl, ascorbyl palmitate or ascorbyl dipalmitate, ascorbic acid alkyl ether such as ascorbyl ethyl ether, ascorbic acid _2-dalcoside or other ascorbic acid dalcoside or the like Ascorbic acid derivatives such as fatty acid esters or tocopheryl phosphate ascorbyl phosphate; vitamins such as tocopherol derivatives such as tocopherol nicotinate, tocopherol acetate, tocopherol linoleate, tocopherol oleanolate, tocopherol oleenolate, tocopherol esterate Derivatives, tocotrienol and the like can be mentioned.

[0059] Anti-inflammatory analgesics include, for example, glycyrrhizic acid or its derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, guaiazulene, allantoin, indomethacin, ibuprofen piconol, ufenamate, suprofen, bufuexamac, or bendazac. Examples include anti-inflammatory agents or steroids such as hydrocortisone acetate or prednisolone.

 [0060] Examples of the antihistamine include diphenhydramine hydrochloride, chlorpheniramine maleate, ketotifen, promethazine, alimemazine, cyproheptadine, homochronorecitalidine, clemastine, or oral latazine.

 [0061] Examples of the antipruritic agent include diphenhydramine hydrochloride, chlorpheniramine maleate, camphor, or substance-gase inhibitor.

[0062] In addition to the above, cosmetic raw material standards, composition standard by cosmetic varieties, Japan Cosmetic Industry Association, ability, table of unnamed cups, INCI Tongue (The International Cosmetic Ingredient Dictionary and Handbook), quasi-drug ingredients Ingredients of known cosmetic ingredients, pharmaceutical ingredients or food ingredients, etc., as well as ingredients listed in the standards, Japanese Pharmacopoeia, standards for pharmaceutical supplements, food additives, etc. It can be contained in a ratio or blending amount. By blending these components, the external preparation for skin according to the present invention is obtained. Various effects can be expected. For example, it is expected to improve the appearance, improve the feeling of use, or improve the stability.

 [0063] The external preparation for skin of the present invention can improve wrinkles. Measure the volume ratio (μ mVmmVlOO), maximum depth (μm), maximum width (μm), number of sheets (NZmm), etc. Can be evaluated. The external preparation for skin of the present invention can exert a beautifying effect. The skin beautifying effect is preferably measured and evaluated by measuring the skin surface (skin) skin pores or the amount of moisture on the skin surface, as described in the following examples. The skin external preparation of the present invention can particularly improve skin texture. Here, the texture is a mesh-like irregularity spreading on the surface of the skin, and the texture includes skin grooves and pores that run like a groove between the skin and the skin. The preparation of the texture includes improving the texture of the skin. For example, the skin and the skin are arranged uniformly, and the skin and the skin are uniformly arranged, for example, in a grid pattern. Or making the pores inconspicuous, and adjusting to a so-called fine skin (for example, increasing the volume ratio of the texture, increasing the number of textures, etc.). The texture state can be evaluated by measuring, for example, the texture volume ratio (μ mVmmVlOO), the texture average depth (μm), or the number of textures (N / mm) according to the description of the following examples. Examples of the method for measuring the moisture content on the skin surface include the measurement of stratum corneum moisture content and the measurement of skin moisture transpiration according to the description in the following examples and the like. The external preparation for skin of the present invention can improve skin sagging. Skin sagging can be evaluated by, for example, measuring skin viscoelasticity according to the description of the following examples.

 [0064] The present invention will be described more specifically below based on examples and test examples, but the present invention is not limited to these.

Example 1 [0065] Cream

 Mineral oil 1 7 g

 White agate serine 5 g

 Seyu Nord 4 g

 Polyoxyethylene (6 0) hydrogenated castor oil 1 8 g

 Triethanolamine 0. 0 7 5 g

 Carboma 0. 0 5 g

 Noelic acid vanillylamide 0.05 0 g

 Edetic acid disodium 0.1

 Methylparaben appropriate amount

 Butylparaben appropriate amount

 Total amount of purified water 1 0 0 g

 Production method: Mineral oil, white petrolatum, cetanol, polyoxyethylene (60) hydrogenated castor oil, methylparaben, butylparaben and nonyl acid vanillylamide are dissolved while heating. Separately, carbomer is dispersed in purified water as an aqueous phase component while heating, and triethanolamine and disodium edetate are added. An oil phase was added to the aqueous phase while stirring and emulsified, and then cooled with stirring to prepare a cream.

 Example 2

 [0066] Cataplasm

 Polyoxyethylene (6 0) hydrogenated castor oil 1 8 g

 Propylene glycol 10 0 g

 Sodium carboxymethylcellulose 50 g

 Nonyl acid vanillylamide 0.05 5 g

 Purified water Total balance of 100 g

 Production method: While heating, mix water, polyoxyethylene (60) hydrogenated castor oil and sodium carboxymethyl cellulose well, and add a solution of propylene glycol and noelic acid bisulamide to dissolve it. Cooling with mixing to prepare cataplasm Example 3

[0067] In Example 1, instead of using 0.005 g of noninolic acid vanillinoleamide, nonylic acid noni]; noramide was added to 0.0001 g, 0.0005 g, 0.001 g, 0.01 g, 0.05 g or 0.005 g. A cream is prepared in the same manner as in Example 1 except that lg is used. Example 4

 [0068] Instead of using 0.005 g of nonyl acid vanillylamide in Example 2, 0.001 g, 0.0005 g, 0.001 g, 0.01 g, 0.05 g, or 0.1 g of f nonyl acid valinoleamide was used. A cataplasm is prepared in the same manner as in Example 2 except that it is used.

 Example 5

 [0069] In Example 1, instead of using polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyethylene glycol monostearate, polyoxyethylene (20) oleyl ether, poloxamer 235, polyoxymer Except for using oxyethylene (7.5) nonyl phenyl ether, polyoxyethylene (60) sorbitol tetraoleate, laurinole dimethylaminoacetate betaine or salt cetyltrimethylammonium, the same as in Example 1. Prepare a cream.

 Example 6

 [0070] In Example 2, instead of using polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyethylene glycol monostearate, polyoxyethylene (20) oleyl ether, poloxamer 235, polyoxymer Except for using oxyethylene (7.5) nonyl phenyl ether, polyoxyethylene (60) sorbitol tetraoleate, laurinole dimethylaminoacetic acid betaine, or salt cetyltrimethylammonium, the same as in Example 2. Prepare a poultice.

 Example 7

 [0071] Ointment

 Mineral oil 2 0 g

 Setanol 9 .9 g

 Polyoxyethylene (6 0) hydrogenated castor oil 1 8 g

 Nonyl acid vanillylamide 0.05 5 g

 White petrolatum Total 1 0 0 g residue

Manufacturing method: Mineral oil, white petrolatum, cetanol, polyoxyethylene (60) hydrogenated castor oil and nonyl acid vanillylamide are mixed with heating to prepare an ointment Example 8 [0072] In Example 7, instead of using 0.005 g of nonyl acid vanillylamide, nonyl acid / 2]; noramide was added to 0.0001 g, 0.0005 g, 0.001 g, 0.01 g, 0.05 g or 0.005 g. An ointment is prepared in the same manner as in Example 7, except that lg is used.

 Example 9

 [0073] In Example 7, instead of using polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyethylene glycol monostearate, polyoxyethylene (20) oleyl ether, poloxamer 235, polyoxymer Except for the use of oxyethylene (7.5) nonyl phenyl ether, polyoxyethylene (60) sorbitol tetraoleate, laurinole dimethylaminoacetic acid betaine, or salt cetyltrimethyl ammonium, the same as in Example 7. Prepare an ointment.

 Example 10

 [0074] Solution

 Polyoxyethylene (60) Hardened castor oil 1 2 g

 Ethanol 2 2 g

 Nonyl acid vanillylamide 0.05 5 g

 Purified water Total balance of 100 g

 Production method: Nonyl acid vanillylamide is added to ethanol and dissolved, and then polyoxyethylene (60) hydrogenated castor oil and purified water are dissolved to prepare a solution.

 Example 11

 [0075] In Example 10, instead of using 0.005 g of nonyl acid vanillylamide, nonyl acid / 2]; noramide was added to 0.0001 g, 0.0005 g, 0.001 g, 0.01 g, 0.05 g or 0.005 g. A solution is prepared in the same manner as in Example 10 except that lg is used.

 Example 12

[0076] In Example 10, instead of using polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyethylene glycol monostearate, polyoxyethylene (20) oleyl ether, poloxamer 235, polyoxymer Other than using oxyethylene (7.5) norphenyl ether, polyoxyethylene (60) sorbitol tetraoleate, laurinole dimethylaminoacetate betaine, or salt cetyltrimethylammonium A solution is prepared in the same manner as in Example 10.

 Example 13

 [0077] Gel agent

 Polyoxyethylene (6 0) hydrogenated castor oil 1 8 g

 Carbopol 9 4 1 0.5 g

 Ethanol 2 2 g

 Triethanolamine 1.5 g

 Nonyl acid vanillylamide 0 0 0 5 g

 Purified water Total of 100 g remaining

 Production method: Polyoxyethylene (60) hydrogenated castor oil and carbopol 941 are added and dissolved in purified water while heating, and then the solution obtained by adding vanillylamide nonyl acid to ethanol is added, and after stirring, triethanolamine is added. In addition, cool with stirring to prepare the gel.

 Example 14

 [0078] In Example 13, instead of using 0.005 g of nonyl acid vanillylamide, nonyl acid / 2]; noramide was added to 0.0001 g, 0.0005 g, 0.001 g, 0.01 g, 0.05 g or 0.005 g. A gel is prepared in the same manner as in Example 13 except that lg is used.

 Example 15

 [0079] In Example 13, instead of using polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyethylene glycol monostearate, polyoxyethylene (20) oleyl ether, poloxamer 235, polyoxymer A gel similar to Example 13 except that oxyethylene (7.5) nouryl phenyl ether, polyoxyethylene tetraoleate (60) sorbit, laurinole dimethylaminoacetate betaine or salt cetyltrimethylammonium is used. Prepare the agent.

 [0080] [Test Example 1]

 Skin primary irritation test

 1.Test substance

 As a test substance, the cream of Example 1 (hereinafter referred to as Cream A) was used.

2.Test method The skin of the back of Japanese white female rabbits was shaved, and the back was sandwiched between the spine and divided into four sections. The two sections that are symmetrical with the back sandwiched between them were made intact skin, and the other two sections were made damaged skin. Injured skin was applied approximately 8 times with adhesive tape (cellophane tape) according to the method of Fukawa et al. [Pharmaceutical Journal, 102 (1): 89-98 (1982)] (until the application site became glossy). Repeatedly, exfoliated and exfoliated. Cream A was applied to intact and damaged skin (2.5cmX2.5cm) with lint cloth and the 0.5gZ section was closed and applied for 24 hours. After 24 hours, the lint cloth with cream A was removed, and the skin condition was evaluated 1, 24, 48 or 72 hours after the removal. The evaluation was performed according to the method of Ikeda et al. [Pharmaceutical research, 1 (1): 23 (1970)] with the skin reaction stimulation scores shown in Table 1. In addition, the average of the obtained stimulation scores (GMIS) was calculated, and the stimulation of the test substance was evaluated according to the following evaluation criteria.

[0081] Evaluation criteria for stimulation:

 GMIS = 0: No stimulation;

 0 <GMIS <2: Mild;

 2≤GMIS <5: Moderate;

 5≤ GMIS: Severe.

[0082] [Table 1] Stimulus score of the captive reaction (Criteria of Ikeda et al.)

 Erythema score

 No erythema 0

 Very mild erythema (only finally recognized) 1

 Evident erythema 2

 Moderate to intense erythema 3

 Strong crimson erythema 4

 Area of crust formation

 No crust formation 0

 Crust formation 1 4 or less 1

 Crust formation 1-4-2 4 2

 Crust formation 2-4-3-3 4 3

 Crust formation 3 4 or more 4

 Edema formation score

 No edema 0

 Very mild edema (finally accepted) 1

 Mild edema (clearly distinguishable from surroundings) 2

 Moderate edema (swells about 1 mm) 3

Strong edema (swells over 1 mm, spreads around) 4 [0083] 3. Test results

 The results are shown in Table 2. After 1 hour of cream A removal, there was very mild erythema (finally visible) on intact and damaged skin, but all recovered by 48 hours. Neither edema nor crust was observed.

 Based on the above, GMIS was 0.2, and the primary skin irritation of Cream A was very weak.

[0084] [Table 2] Test substances

[0085] [Test Example 2]

 Rabbit eye mucous membrane irritation

 1.Test substance

 Cream A was used as the test substance.

 2.Test method

 A single dose of cream AO.lmL was administered into the conjunctival sac of a Japanese white female rabbit, and the eye was washed and divided into two groups. In the eye wash group, after applying Cream A, the eyes were closed for about 30 seconds, and then the anterior eye part was washed with 75 mL of physiological saline for about 30 seconds (25 mL / l0 sec). In the non-eyewash group, after cream A administration, the upper and lower eyelids were gently pressed and closed for about 1 second. The cornea, iris and conjunctiva were evaluated according to Table 3 1, 24, 48 or 72 hours after administration of Cream A. In addition, corneal staining was performed with fluorescein 24 hours after administration of Cream A, and the presence or absence of corneal damage was observed. That is, after adding 1 drop of physiological saline to the fluorescein sodium application part of the Flores (registered trademark; Menicon Co., Ltd.) test paper, it is brought into contact with the conjunctival sac of both eyes, and fluorescein sodium is added to both. Moved to eyes. Excess fluorescein sodium was thoroughly washed away with physiological saline. The interior of the room was squeezed, and the presence of corneal damage was observed with a slit lamp fitted with a blue filter.

[0086] [Table 3] Site Evaluation of eye reaction

1. Cornea (A) Degree of turbidity

 Transparent, no turbidity 0 Scattered and chronic turbid, Iris is visible 1 Translucent and easily identifiable, Iris is slightly indistinct 2 Milky, Iris pattern is not recognized, pupil size is finally recognized 3 White turbidity , Iris is not allowed 4

(B) Corresponding corneal opacity area

 0 0

0 <Area 4 4 1 1 Z4≤Area 1/2 1/2 1 / 2≤Area 3/4 3 3 4≤Area≤ 4

2. Iris (A) Normal 0

 Unusual folds, depressive blood, swelling, pericorneal hyperemia

 One or a combination), with some light response 1 without light response, bleeding, significant tissue collapse (any one 2)

 3. Conjunctiva (A) Redness of conjunctiva (eyelid conjunctiva and bulbar conjunctiva)

 Blood vessels are normal 0 Blood vessels are clearly more red than normal 1 Chronic, deep red and individual blood vessels are difficult to distinguish 2 Chronic beef-like red 3

(B) Conjunctival edema

 No swelling 0 Swelling than normal (including nictitating membrane) 1 Obvious swelling, eyelid slightly valgus 2 Swelling, eyelid half closed 3 Swelling, eyelid more than half closed 4

(C) secretion

 No secretion 0 Slightly more than normal (recognized in the dance angle of normal animals)

 1) There are secretions, and the eyelids and the nearby hair are also wetted. 2 There are secretions, and a considerable portion of the hair around the eyelids.

 Wet 3

1. Cornea = A X B X 5 (Max 80 points)

 2. Iris = A X 5 (Maximum 10 points)

 3. Conjunctiva = (A + B + C) X 2 (maximum 20 points)

 S c o r e = 1 + 2 + 3

3.Test results

The results are shown in Table 4. No irritation due to Cream A was observed in either the eyewash group or the non-eyewash group. In addition, corneal staining positive in observation by corneal staining No eye was observed. From the above results, it was found that Cream A is a safe cream without irritation and risk of corneal damage.

 [Table 4] Eye mucosal irritation test results

 *: Before application

 * *: 24 hours after application.

[0089] [Test Example 3]

 Effect on human skin

 1.Test substance

 Cream A was used as a test substance. As a control substance, Coenzyme Q10 (Ubiquinone) -containing cream (Vital Age Q10 cream (manufactured by Kose Cosmetics Co., Ltd.); hereinafter referred to as Cream B) was used.

 2. Subject:

 Informed consent was conducted in accordance with the criteria for conducting pharmaceutical clinical trials, and screening was conducted from 46 female subjects who obtained their written consent, and the following selection criteria were met, and the exclusion criteria were not violated. Les, 20 subjects were selected as subjects for this study. The age of 20 female subjects was 42. 2 ± 4.2 years. During the test period, I was allowed to avoid irregular activities (eg, lack of sleep, heavy drinking and eating out). Meal * Exercise was maintained in the same quantity and quality as in daily life before the start of this study. During the test period, changes to cosmetics currently in use were prohibited. During the test period, the use of moisturizing cream for night skin care was prohibited.

[0090] Selection criteria:

Japanese women aged between 35 and 50; Those who are worried about the eyelids;

 Those who are concerned about sagging skin;

 Those with dry skin;

 Those who can fill out self-diagnosis documents, etc .;

 Those who can visit the designated facility on the scheduled visit date.

 Exclusion criteria:

 Those who are taking or applying medicines that may affect the test results; those who regularly eat health foods that may affect the test results; Who may be breastfeeding and breastfeeding;

 Have excessive consumption of alcohol;

 Who may have allergic symptoms;

 Those whose skin condition at the application site may affect the evaluation;

 Participants in other clinical trials;

 With severe anemia;

 Others who are deemed inappropriate by the study supervisor to conduct this study.

 [0091] Single-blind controlled comparative study (left-right comparison):

 The subjects were assigned so that (1) skin wrinkle volume ratio, (2) skin elasticity, and (3) moisture content of the skin of each subject's right face were as identical as possible in each group. Group composition was performed.

[0092] [Table 5] Group composition

3.Test method

Apply 0.5g of Cream A and Cream B once a day after washing or bathing, and evenly applying to each half-face (shadow part in Fig. 1) for 8 weeks before going to bed. According to the schedule shown in Fig. 2, skin was observed every week. Observations were made on skin moisture retention, skin elasticity, wrinkles, texture and pores. Specifically, skin moisture transpiration measurement (described later) Moisturizing), skin moisture measurement (moisturizing), skin elasticity measurement, skin replica image numerical analysis, texture replica image numerical analysis and pore opening image numerical analysis. At the same time, according to the skin condition of the subject, the subjective symptoms of the subject were scored based on the criterion (7) below.

 [0094] Observation was carried out after washing the face in an environmental adjustment room (humidity 50% ± 15%, room temperature set to 22 ° C ± 2 ° C) for 30 minutes.

 [0095] (1) Measurement of skin moisture transpiration (left and right):

 Measures transpiration of skin at 4 cm from the base of the right ear (and left ear), connecting the root of the right ear (and left ear) and the right lip (and left lip) of the subject. did. The measurement was performed with Tewameter TM 300 (manufactured by Integral Co., Ltd.). The Tewameter ™ 300 is a device that measures transcutaneous water transpiration (TEWL) from the mass of water moving in a cylindrical probe per unit time based on the diffusion law.

 [0096] (2) Skin moisture measurement (left and right)

 Connect the bottom of the subject's right earlobe (and left earlobe) and the right lip (and the left lip), and measure the skin moisture at three locations, 5cm, 5.5cm, and 6cm from the bottom of the earlobe. The value was calculated. The measurement was performed with CORNEOMETER CM 825 (manufactured by Integral Co., Ltd.). The CORNEOMETER CM 825 is a device that measures the stratum corneum moisture content of the skin using the capacitance method based on the difference in dielectric constant between water and other substances.

 [0097] (3) Skin elasticity measurement (left and right)

 The viscoelasticity of the skin was measured at 4 cm from the root under the right ear heel (and left ear lip), connecting the root of the right ear heel (and left ear heel) and the right lip end (and left lip end). . The measurement was performed with CUTOMETER MPA580 (manufactured by Integral Co., Ltd.). The CUTOM ETER MPA580 measures skin viscoelasticity based on the suction height (maximum amplitude value, minimum amplitude value) when the skin is sucked at a constant negative pressure, and the return rate of the skin when the pressure is released. Device.

 [0098] (4) Texture replica image 'Numerical analysis (left and right)

The rebris was collected from the bottom of the right earlobe (and left earlobe) to the right nose and 7 cm from the bottom of the earlobe. Reflected replica analysis system ASA — It was conducted at 03R (manufactured by Asahi Biomed Co., Ltd.). Image analysis of replicas for reflection Replica analysis system ASA-03R uses a CCD (imaging device) camera to capture shadow images according to the shape of the texture obtained by irradiating the sampled replica with parallel light at an angle of 30 ° Then, the volume ratio or the number of textures can be measured by importing into a computer and processing the image.

 [0099] (5) Shizu replica image 'Numerical analysis (left and right)

 Replicas were collected at the left and right eye corners. The images and analysis of the collected replicas were performed with a reflection replica analysis system ASA-03R (manufactured by Asahi Biomed Co., Ltd.). The reflection replica analysis system ASA-03R uses a CCD camera to capture a shadow image corresponding to the shape of the ridge obtained by irradiating the collected replica with parallel light at an angle of 30 °, and captures the captured image into a computer. By performing image processing, the sheet volume ratio, the maximum sheet depth, the maximum sheet width, or the number of sheets can be measured.

[0100] (6) Pore opening image 'Numerical analysis

 The facial image analyzer VISIA (Integral Co., Ltd.) took color photographs and UV photographs of the pores on the left and right sides of the face, and analyzed the number of pores based on the computer system based on the obtained photos.

[0101] (7) Criteria for distinguishing subjective symptoms

 Subject's subjective symptoms were scored according to the discrimination criteria in Table 6.

[0102] [Table 6]

Symptom criteria

 "I don't care at all": "I don't care so much": 2, "I can't say anything about" Sobas "", 3, "I'm a little worried": 4, "I'm very worried": 5 .

"I don't care at all J: 1," I don't really care about j: 2, "I can't say anything about Jiji, J: 3,"I'm a little worried ": 4,"I'm very worried ": ₅ Calculated.

 "I don't care at all": 1, "I don't care": 2, "I can't say anything about the bulkiness of my face": 3, "I'm a little worried": 4, "I'm very worried ": Calculated as 5.

 "I don't care at all": 1, "I don't care much": 2, "I can't say anything about the texture of my eyes and mouth": 3, "I'm a little worried": 4, "I'm very worried": Calculated as 5.

 "I don't care at all J: 1," I don't care much ": 2," I can say either, I don't have a feeling of tingling after washing my face J: 3, "I'm a little worried j: 4," I'm very worried ": Calculated as 5.

 "I don't care at all": 1, "I don't care much": 2, I can't say anything about Γ J: 3, "A little worried J: 4," "Very worried": 5 .

 "I don't care at all": 1, "I don't care much J: 2,"

Not calculated for T-zone stickiness: 3; “Somewhat worried J: 4”, “Very worrisome”: 5

 "I don't care at all": 1, "I don't care much": 2, "I don't care about pimples": 3, "I'm a little worried": 4, "I'm very worried": 5 Calculated.

 "I don't care at all" J: 1, "I don't care much": 2, "I don't care about the bear in my eyes": 3, "I'm a little worried": 4, "I'm very worried": 5 Calculated.

 "I don't care at all": 1, "I don't care much": 2, "I don't care about the dullness of the whole face": 3, "I'm a little worried": 4, "I'm very worried about J: 5 Calculated as

 "I don't care at all J: 1," I don't care much ": 2," I can't say anything about the badness of makeup ": 3," I'm a little worried ": 4," I'm very worried ": Calculated as 5.

[0103] 4. Statistical analysis

 Within the group, Dunnett's t test indicated a significant difference of 5% or less. A comparison between cream A and cream B was a significant difference of 5% or less using a paired t test. Questionnaire items were compared with Wilcoxon's signed rank test (multiple comparison with Bonferroni's inequality correction), with 5% or less being significant.

[0104] 5. Test results

 (1) Skin moisture transpiration and skin moisture

 Skin moisture transpiration was higher in both the cream A administration group and the cream B administration group in the final observation period after application than before application, but no significant difference was observed.

 [0105] With regard to the amount of skin moisture, a relatively high value was observed in the cream A administration group compared with before application in almost all observation periods after application, but no significant difference was observed. On the other hand, the cream B administration group showed significantly higher values than before application in almost all observation periods after application, and there was a significant difference between the group and the cream A administration group 2 weeks after application.

 [0106] From the above results, it was found that Cream A showed a tendency to improve skin moisture retention.

[0107] (2) Pore In both the cream A administration group and the cream B administration group, the number of skin pores before application and the number of pores after application did not change significantly, and there was no significant difference between the two groups.

 [0108] (3) Skin elasticity

 The results of skin viscoelasticity measurement are shown in Table 7. In terms of skin elasticity, the maximum amplitude value was significantly higher in both the cream A administration group and the cream B administration group than before application in almost all observation periods after application. The return rate was significantly higher in the cream A administration group and the cream B administration group in all observation periods after application. As a result, it was found that Cream A has the same skin elasticity improving effect as that of the cream containing Coenzyme Q10, which gives the skin tension and improves skin sagging.

 [0109] [Table 7]

 Elasticity

[0110] (4) Changes in texture

 Test replicas analyzed with the replica replica analysis system ASA-03R for reflection of texture images The value of the texture volume ratio or number of textures after application is divided by the respective values before application, and the value before application is defined as 1. Was calculated as a texture volume ratio (relative value;%) or texture number relative value (%). The results are shown in FIG. 3 or FIG. The texture volume ratio and the number of textures were significantly higher than those before application in all observation periods after application in both the Group A administration group and the Cream B administration group. The value was higher in the cream A administration group than in the cream B administration group.

[0111] Since the texture is a mesh-like irregularity spreading on the surface of the skin, when the texture becomes finer, Volume ratio and texture number increase. Therefore, from the above results, it was found that the external preparation for skin of the present invention has a greater effect of strengthening the texture of the skin than the cream formulated with Coenzyme Q10.

 [0112] (5)

 Divide the specimen replica image with reflection replica analysis system ASA-03R and divide the specimen volume ratio or number of specimens after application by the respective values before application, and set the value before application as 1. Each value was calculated as the volume ratio (relative value;%) or the number of sheets (relative value;%). The results are shown in FIG. 5 or FIG. The volume ratio and the number of seeds were significantly lower in the cream A administration group and the cream B administration group in all observation periods after application than before application. The value was lower in the cream A administration group than in the cream B administration group.

 [0113] From the above results, it was found that the external preparation for skin of the present invention had a greater effect of improving the skin tone than the cream containing Coenzyme Q10.

 [0114] (6) Subjective symptoms

 Table 8 shows changes in subjective symptoms according to Table 6. As a result, the entire face is thick and sagging, the T-zone is sticky, and the pimples are pimples. The subject's subjective symptom of poorness was significantly lower in both the cream A administration group and the cream B administration group than before application in all observation periods after application. In addition, the score values of the subjective symptoms of the eyes, the mouth roughness, the feeling of feeling after washing the face, and the bears of the eyes decreased with the passage of time in the cream A administration group and the cream B administration group. Some of the cream B administration groups showed significantly lower values than before application. No significant difference was found between the cream A administration group and the group. This indicates that there is no difference in the effects of cream A and cream B on the subject's subjective symptoms.

[0115] [Table 8]

Average standard deviation

 * Signed rank test of Wilcoxon (multiple comparison with correction by Bonferroni's inequality) was performed before and after application. *: P <0.05, **: P <0.01, ***: P <0.001

I understood that it is better than Q10. Further, it was found that the external preparation for skin according to the present invention significantly improves the subjective symptoms related to the bulkiness of the entire face. This is because the skin moisture content did not increase significantly, but it was related to the increase in skin moisture content after applying Cream A compared to before applying Cream A, and the subject realized that the increase provided a moisturizing effect. It was thought that. With regard to spots, it is generally known that a decrease in skin moisture content causes dryness of the skin, and it is generally known that dryness of the skin causes stains. It was suggested that it has the effect of preventing or improving.

 [0117] [Test Example 4]

 Correlation between blood circulation promoting effect of nonyl acid vanillylamide and improvement of wrinkles, skin sagging or skin texture

[0118] 1. Test substance

 The following creams (a) to (c) were used as test substances.

 (a) Nonyl acid vanillylamide 0.001 mass% cream: A cream prepared using nonyl acid vanillylamide 0. OOlg as described in Example 3.

(b) nonyl acid Banirinoreamido 0.005 mass _^0/0 containing creams: cream of Example 1.

(c) Nonyl acid vanillylamide 0.1 mass% cream: A cream prepared using nonyl acid vanillylamide 0.1 g according to the description in Example 3.

 [0119] 2. Experimental method

 (1) Examination of effects on skin blood flow

 Apply the cream (a) to (c) of the test substance to the inner part of the forearm once, and apply the drug using a laser blood flow meter Cyber Med CDF_2000 (manufactured by Cyber Farm Co., Ltd.). Blood flow on the skin surface of the cream application area was measured before and 30 minutes after application. The measured value was calculated with the value before application as 1, and the value after 30 minutes of application as the relative value (ratio).

[0120] (2) Improvement of wrinkles, skin sagging or skin texture

Skin sagging was determined by measuring skin elasticity. Apply the creams (a) to (c) of the test substance to the face for 1 week, and use Super Skin Checker MC_SSC ( Japan Esthetic Association) was used to measure the elasticity of the skin surface of the cream applied part before and 1 week after application of the cream. The measured value was calculated with the value before application of the cream as 100% and the value one week after application of the cream as the relative value (%).

 [0121] Skin texture was photographed before and 1 week after application of the cream with a super skin checker MC-SSC built-in CCD camera. The effect was judged by visual confirmation of the photograph taken.

[0122] Using a digital camera E ○ S _Kiss Digital N (Canon, Inc.), Shizu was photographed at the same angle and with the same amount of light before and after applying the cream. . The effect was judged by visual confirmation of the photograph taken.

[0123] 3. Experimental results

 (1) Effects of nonyl acid vanillylamide on skin blood flow

 The effect of nonyl acid vanillylamide on skin blood flow is shown in FIG. In the group with cream applied with 0.1% by mass of vanillinamide of noelate (n = 9), the increase was 0.001% by mass.

Compared with the% cream containing group (n = 9) and 0.005 mass% containing cream group (n = 18), the value was significantly higher.

[0124] (2) Effects of cream containing nonyl acid vanillylamide on skin

 (i) Elasticity

Table 9 shows the skin elasticity effect of nonyl acid vanillylamide. In nonyl acid Banirinore amide 0.001 mass _^0/0 containing cream applied group (n = 9) or nonyl acid vanillylamide 0.0 05 wt% containing cream applied group (n = 18), was applied 1 week cream Later, an increase in skin elasticity (improvement of skin sagging) was observed compared to before application of the cream. However, the Noninore acid Banirinoreamido 0.1 mass _^0/0 containing cream applied group (n = 9), change in elasticity has failed substantially observed.

[0125] [Table 9]

 Relative

 Cream II! (%)

Before application After application Nonyl acid vanillylamide 0.00 ¹ % by weight containing cream 1 00 1 1 3.8 Nonyl acid vanillylamide 0.005 Imposition 1½ containing cream 1 00 1 1 6.7 Nonyl acid vanillylamide 0.1 mass ^0/6 containing cream 1 00 99.4 [0126] (ii) Texture improvement effect

Table 10 shows the results of classification of the improvement effects for each treatment group, assuming that the texture as shown in the photograph in Fig. 8 was improved. In nonyl acid vanillylamide 0.001 wt% containing cream applied group _(n = 9) or nonyl acid vanillylamide 0.005 mass _^0/0 containing tally beam agent applied group (n = 18), after applying 1 week cream , Skin texture was markedly improved compared to before cream application. In the nonylic acid vanillylamide 0.1 mass% cream application group (n = 9), however, almost no improvement in skin texture was observed.

 [0127] Based on these results, the results of calculating the texture improvement rate of the cream containing 0.0001% by mass, the cream containing 0.025% by mass and the cream containing 0.05% by mass are shown. Shown in 11. In any case, it is considered that an effect more than improvement can be expected.

[0128] [Table 10]

[0129] [Table 11]

 [0130] (iii) Wrinkle improvement effect

 Table 12 shows the results of classification of the improvement effects for each treatment group, assuming that the cases shown in the photographs in Fig. 9 were improved. In the nonylic acid vanillylamide 0.005 mass% cream application group (n = 18), after applying the cream for 1 week, a significant improvement in wrinkles was observed compared to before application of the cream. In the vanilla amide containing 0.001% by mass of cream (n = 9), improvement in wrinkles was also observed compared to before cream application. However, in the nonylic acid vanillylamide 0.1 mass% cream application group (n = 9), almost no improvement was observed in wrinkles.

[0131] On the basis of these results, a cream containing 0.0001% by mass, containing 0.025% by mass Table 13 shows the results of calculating the wrinkle improvement rate of the cream and 0.05% by mass-containing cream. Although the improvement rate was slightly lower than 25% for the cream containing 0.001% by mass, an effect more than the improvement can be expected with the cream containing 0.025% by mass or the cream containing 0.05% by mass. it is conceivable that.

 [Table 12]

 [0133] [Table 13]

 [0134] From the results described above, the skin texture improvement, wrinkle or sagging amelioration action of the external preparation for skin according to the present invention is exhibited by nonyl acid vanillylamide in a specific low concentration region, and blood circulation of nonyl acid vanillylamide is achieved. It turned out that there was no correlation with the promoting action. Industrial applicability

[0135] The external preparation for skin of the present invention is useful as a pharmaceutical or cosmetic product having an effect of improving skin texture disturbance, wrinkle improvement or skin sagging.

Claims

The scope of the claims

 [1] Skin that improves skin texture disorder, wrinkles or sagging, characterized by containing nonyl acid vanillylamide as an active ingredient in an amount of 0.0001% by mass or more and 0.05% by mass or less based on the total amount of the external preparation for skin. Topical agent.

 [2] The skin external preparation according to claim 1, which is an external skin preparation for improving skin texture disorder.

 [3] The external skin preparation according to claim 1, which is an external skin preparation for improving wrinkles or skin sagging.

 [4] The external preparation for skin according to any one of claims 1 to 3, further comprising a nonionic surfactant.

 [5] Formulation power of nonylic acid vanillylamide and nonionic surfactant Non-ionic surfactant is 50 to 30000 parts by mass with respect to 1 part by mass of nonylic acid vanillylamide. .

 [6] Nonionic surfactant power S, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkyl The skin external preparation according to claim 4 or 5, wherein the preparation is at least one selected from phenyl ether and polyoxyethylene sorbite fatty acid ester.

 [7] The topical skin preparation is in the form of a liquid, suspension, emulsion, cream, ointment, gel, liniment, lotion, cataplasm or pack. The topical skin preparation according to any one of 1 to 6 above.

 [8] The external preparation for skin according to any one of claims 1 to 7, wherein the external preparation for skin is a cosmetic.

[9] A topical skin preparation containing 0.001% by mass or more and 0.05% by mass or less of nonyl acid vanillylamide as an active ingredient is applied to the skin of mammals including humans. A method for improving skin texture disturbance, a method for improving wrinkles, or a method for improving skin sagging. Non-succinic vanillylamide as an active ingredient is 0.0001% by mass or more and 0.05% by mass or less based on the total amount of external preparations for external use for improving skin texture, itchiness or sagging of skin. Of nonylic acid vanillyl amide for the manufacture of an agent.